Elsevier

Biological Psychiatry

Volume 78, Issue 8, 15 October 2015, Pages 582-589
Biological Psychiatry

Archival Report
Dorsomedial Prefrontal Cortex Mediates the Impact of Serotonin Transporter Linked Polymorphic Region Genotype on Anticipatory Threat Reactions

https://doi.org/10.1016/j.biopsych.2014.07.034Get rights and content

Abstract

Background

Excessive anticipatory reactions to potential future adversity are observed across a range of anxiety disorders, but the neurogenetic mechanisms driving interindividual differences are largely unknown. We aimed to discover and validate a gene-brain-behavior pathway by linking presumed genetic risk for anxiety-related psychopathology, key neural activity involved in anxious anticipation, and resulting aversive emotional states.

Methods

The functional neuroanatomy of aversive anticipation was probed through functional magnetic resonance imaging in two independent samples of healthy subjects (n = 99 and n = 69), and we studied the influence of genetic variance in the serotonin transporter linked polymorphic region (5-HTTLPR). Skin conductance and startle data served as objective psychophysiological indices of the intensity of individuals’ anticipatory responses to potential threat.

Results

Threat cues signaling risk of future electrical shock activated the dorsomedial prefrontal cortex (dmPFC), anterior insula, bed nucleus of the stria terminalis, thalamus, and midbrain consistently across both samples. Threat-related dmPFC activation was enhanced in 5-HTTLPR short allele carriers in sample 1 and this effect was validated in sample 2. Critically, we show that this region mediates the increase in anticipatory psychophysiological reactions in short allele carriers indexed by skin conductance (experiment 1) and startle reactions (experiment 2).

Conclusions

The converging results from these experiments demonstrate that innate 5-HTTLPR linked variation in dmPFC activity predicts psychophysiological responsivity to pending threats. Our results reveal a neurogenetic pathway mediating interindividual variability in anticipatory responses to threat and yield a novel mechanistic account for previously reported associations between genetic variability in serotonin transporter function and stress-related psychopathology.

Section snippets

Methods and Materials

Studies were approved by local medical ethical committees from Radboud University Medical Centre and University Medical Centre Utrecht (UMCU), respectively.

Subject Descriptives

For sample 1, genotype distribution was in accordance with previous studies and in Hardy-Weinberg equilibrium (p = .36). As intended, selection led to a higher proportion of homozygotes in sample 2 (Table 1). There were no significant differences in either experiment between the genotype groups with regard to sex distribution, age, and trait anxiety (all p values > .09; Table 1). Given that subjects in sample 1 were all male subjects, sex was controlled for in the genotype analyses reported

Discussion

The identification of neurobiological pathways underlying interindividual differences in psychophysiological reactions during the anticipation of adversity has the exciting outlook of uncovering fundamental mechanisms that might determine vulnerability to anxiety disorders. Here, we validate across two independent samples with different experimental setups that a genetic variation in the 5-HTTLPR predicts psychophysiological reactions to threat mediated by its impact on neural processing in the

Acknowledgments and Disclosures

FK, MK, JLK, GvW, GF, and JMPB designed the experiments. FK and MK performed data analyses. BF, IH, RSO, and FK were responsible for genetic analyses. FK, MK, GF, and JMPB wrote the article. All authors commented on previous versions of the manuscript and agreed upon the final version of the manuscript.

This work was supported by funding from the Dutch organization for scientific research (NWO) through grants awarded to GF (VIDI grant) and GvW (VENI grant). We acknowledge technical assistance

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  • Cited by (0)

    1

    Authors FK and MK contributed equally to this work.

    2

    Authors GF and JMPB contributed equally to this work.

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